Surface analysis of cannabigerol cocrystals: linking crystal structure to enhanced properties

This study investigates the solid forms of cannabigerol and identifies two new cocrystals, showing significant improvements in physicochemical properties. The findings highlight the strong predictive capability of surface interaction parameters for aqueous dissolution, offering valuable insights for pharmaceutical development.

Cannabigerol is a bioactive compound derived from Cannabis sativa. It displays many promising pharmaceutical and nutraceutical properties. Its use and research are complicated by its thermally unstable solid form with low solubility and needle habit, preventing easy formulation into tablets or capsules. To overcome these problems, we conducted a crystallization screening with the aim to discover new crystal forms with enhanced properties. Though polymorph and solvate screenings did not yield new forms, the cocrystal screening was successful. Two cocrystals were discovered, one with piperazine and another with tetra­methyl­pirazine, both in a 1:1 ratio. The latter can exist in three polymorphic forms. Both offer improvements in the melting point and crystal habit, and the cocrystal with tetra­methyl­pirazine also shows a significant enhancement in dissolution rate. The new solid forms were analysed by a combination of methods, including X-ray powder diffraction, nuclear magnetic resonance spectroscopy, differential scanning calorimetry, thermogravimetric analysis and intrinsic dissolution rate. Single-crystal X-ray diffraction data were used to solve the crystal structures, which were then compared with that of pure CBG. The crystal morphologies and surfaces were comprehensively analysed using the CSD-Particle suite, with various properties correlated against dissolution rates. While surface attachment energy and roughness (rugosity) did not show significant effects, the concentration of unsatisfied hydrogen-bond donors displayed a positive correlation. There were two parameters with a very strong correlation to dissolution rate: the propensity for interactions with water molecules, determined by the maximum range in the full interaction maps on the surface calculated for the water probe, and also the difference in the positive and negative electrostatic charges. These parameters proved highly predictive of aqueous dissolution, offering immense utility in pharmaceutical development.